1. Field of the Invention
The present invention is concerned with an improved method of preparing salicylic acid and derivatives thereof employing as a starting material acetoxyphenyl, or a derivative thereof suitable for preparing the desired derivative of salicylic acid.
More particularly, the present invention is concerned with preparation of 2',4'-difluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylic acid, an important anti-inflammatory and analgesic therapeutic agent.
2. Description of the Prior Art
Industrial preparation of salicylic acid has long been carried out by the Kolbe-Schmitt reaction in which sodium phenoxide and carbon dioxide are heated at 120.degree.-140.degree. C. under pressure. A small amount of the p-derivative is formed at the same time, and if the temperature rises above 140.degree. C., the p-isomer is the main product. The Kolbe-Schmitt reaction, in turn, is one step in a potentially important process of preparing 2',4'-difluoro-4-hydroxy-[1,1'-biphenyl]-3-carboxylic acid, referred to above. See U.S. Pat. No. 3,992,459. In that process, the intermediate which is converted to the starting material for the Kolbe-Schmitt reaction is a phenyl acetate ester. Accordingly, that process is characterized by the disadvantages of involving cumbersome ester saponification and requiring sodium salt isolation, with attendant drying problems. Thus, the method of the present invention constitutes an improvement of that potentially important process whereby the described disadvantages are avoided and one step is removed from the overall process.
It is known to carry out selective cleavage of aryl esters with anhydrous alkali carbonates. See H. E. Zaugg, J. Org. Chem., Vol. 41, No. 21, (1976) 3419-3421. However, knowledge of this process would not have suggested the novel improvement of the phenyl ester to salicylic acid process accomplished by the method of the present invention, with the unexpected result of achieving a facile, one-step preparation characterized by high yields.